Devices and methods for prevention, moderation, and/or treatment of cognitive injury

ABSTRACT

This disclosure describes methods and systems for preventing, moderating, and/or treating brain injury. The methods herein may include obtaining a test result reflecting a condition of a brain in the subject, determining a stimulation parameter based on the test result, and stimulating a nerve based on the stimulation parameter, wherein stimulation of the nerve assists or causes contraction of a respiratory muscle in the subject. The systems herein may include a processor configured to: receive a test result reflecting a condition of a brain in a subject, and determine a stimulation parameter based on the test result; and a stimulator configured to stimulate a nerve based on the stimulation parameter, wherein stimulation of the nerve assists or causes contraction of a respiratory muscle in the subject.

CROSS-REFERENCE

This application claims priority to U.S. Provisional Application No.62/527,536, filed on Jun. 30, 2017, the entire disclosure of which ishereby incorporated by reference in its entirety.

In general, all publications, patent applications, and patents mentionedin this specification are herein incorporated by reference in theirentirety to the same extent as if each individual document wasspecifically individually indicated to be incorporated by reference.

TECHNICAL FIELD

The embodiments of this disclosure generally relate to methods, systems,and devices for the diagnosis, mitigations, and treatment of cognitiveinjury (e.g. mechanical ventilation induced delirium, stroke,concussion, etc.). In some examples, the present disclosure is directedto a method of reducing the occurrence of brain cell damage or death ina subject. One exemplary aspect is directed to a method of reducing theoccurrence of brain cell damage or death caused by transient cerebralhypoxia/ischemia condition, brain inflammation condition, or a traumaticbrain injury (TBI) event. Another exemplary aspect is directed todevices, systems, and methods for reducing brain and/or cognitive injuryin patients on mechanical ventilation. Yet another exemplary aspect isdirected to mitigating diaphragm muscle, lung, and brain injury.

BACKGROUND

Critical care patients, particularly those requiring invasive mechanicalventilation (MV), often experience higher levels of diaphragm, lung,brain, and other organ injury. The diaphragm muscle may rapidly losemuscle mass and strength. The lungs may suffer from ventilator-inducedtrauma. Cognitive effects may be caused by several factors includingaberrant neuro-signaling and inflammatory responses. Patients presentingwith existing cognitive injury such as, for example, from a traumatic(e.g. concussion) or ischemic (e.g. stroke) brain event may be at aneven greater risk for rapid cognitive deterioration once placed on MV.There remains a need for cost-effective, practical, surgically simpleand minimally invasive apparatus and methods that may reduce diaphragm,lung, and cognitive injury (e.g. delirium, dementia, and cognitivedysfunction, etc.) in ICU patients, particularly for those patients onMV.

During natural breathing, the diaphragm and other respiratory musclescontract to create a region of negative pressure outside the lungs. Thelungs expand to equalize pressure, and air naturally flows into thelungs. When air is flowing into the lungs, this is inhalation, the actof breathing in. Most mechanical ventilators help patients breathe byassisting the inhalation of oxygen into the lungs and the exhalation ofcarbon dioxide by using positive pressure to periodically pressurizeand/or inflate the lungs. While lifesaving in many respects, MV may alsobe detrimental.

For example, MV may induce Ventilator Induced Lung Injury (VILI),including, for example, volutrauma, atelectrauma, and biotrauma.Volutrauma is damage from over-distension of the lung parenchyma, whichmay result from high tidal volume and/or low lung compliance.Atelectrauma may result from recruitment-decruitment of collapsedalveoli during each ventilator cycle, generally a result of low tidalvolume (Vt), low pressure, or inadequate levels of Positive EndExpiratory Pressure (PEEP). Biotrauma is the expression of a localinflammatory process and may be characterized by the release ofinflammatory mediators because of over-distending tidal volumes andrepetitive opening and closing of unstable lung units.

Lung injury may lead to the activation of inflammatory genes and therelease of inflammatory mediators from cells in the lungs. Cyclicstretch (CS) of the lung tissue may cause inflammatory cellinfiltration, which may contribute to loss of capillary-alveolar barrierfunction, increased expression of pro-inflammatory mediators, includingtumor necrosis factor-α and IL-6, and induction of cellular apoptosis.As free inflammatory mediators originating from the lungs circulatethrough the organs of the body, the free inflammatory mediators mayimpair oxygen delivery and may lead to organ failure. MV may contributeto compartmentalization of lung inflammatory response leading tomultiple organ dysfunction syndromes. Thus, MV induced stress and strainin the lungs may result in inflammatory response of the alveoli,recruitment of neutrophils to lung parenchyma, and the production ofcytokines. This process may then spread into intravascular circulationsystems, and may reach distal organs, such as, for example, the brain.

Further, the lungs may sense the MV induced mechanical stimuli bymechanoreceptors, and the lung may communicate this information to thebrain, via the autonomic nervous system. The diaphragm has significantsensory innervations.

Generally, the goals of mechanical ventilation are to provide precisecontrol of the respiratory variables, such as, for example, partialpressure of arterial oxygen (PaO₂) and partial pressure of arterialcarbon dioxide (PaCO₂) control. The mechanical ventilator may cyclicallypressurize the lungs to provide effective gas exchange. It is importantto balance goals with minimizing lung stretch and minimizing lower lungcollapse. The unique lung volume, lung compliance, and gas exchangerequirements for each patient may complicate these goals.

Decreased tidal volumes may lead to hypercapnia (increased PaCO₂).Hypercapnia may lead to intracranial hypertension. Improved systemicoxygenation may reduce brain hypoxic insults. However, excessively highventilator pressures may lead to systemic inflammatory response, which,in turn, may affect cerebral oxygenation and metabolism, therebyinducing brain injury.

PEEP may be used to recruit previously collapsed alveoli, improvearterial oxygenation, and reduce elastance of the respiratory system.However, PEEP may be detrimental to gas exchange, decrease cardiacoutput by reducing aortic blood flow/pressure, and may lead tobarotrauma.

Protective mechanical ventilation with moderate to lower tidal volumes(e.g. 6 mL/kg), limiting plateau pressure <30 cm H₂O, and utilizing PEEPof 10 cm H₂O versus higher Vt and no PEEP may lead to less lunginflammation and reduce mortality. However, a single ventilationapproach likely does not fit all scenarios. Even for a single patient,it may be difficult to balance diaphragm protection, lung protection,and brain protection, and provide adequate gas exchange for the patient.As such, clinicians may be forced to use balanced approaches, makingtradeoffs and accepting potential injury to one organ while reducing thelikelihood of injury to another organ.

Thus, there remains a need to limit or reverse lung injury formechanically ventilated patients.

Although MV can be a life-saving intervention for patients sufferingfrom respiratory failure, prolonged MV can promote diaphragmatic atrophyand contractile dysfunction (VIDD). This type of diaphragm injury andthe accompanying diaphragm weakness may contribute to difficulty inweaning from MV.

The majority of patients treated with MV are readily liberated fromventilator support upon resolution of respiratory failure or recoveryfrom surgery, but approximately one-third of patients encounterchallenges with regaining the ability to breathe spontaneously. Theprognosis may be favorable for patients who wean from MV successfully atthe first attempt, but is less so for the remaining patients.

To date, there remains an unmet need to limit or reverse the diaphragminjury for mechanically ventilated patients.

The diaphragm muscle is an important crossroad for information involvingthe entire body. In addition to serving as the primary respiratorymuscle, it has links throughout the body as part of an informationnetwork necessary for breathing. The diaphragm has significant sensoryinnervations. Both the phrenic and vagus nerves are part of thisnetwork, and each nerve contains both sensory and motor fibers. As anexample, the vagus nerve which innervates the crural region of thediaphragm, can directly affect the system of reciprocal tensionmembranes (e.g. dura), producing a range of relevant symptoms in thebody. In a similar mechanism, the event of diaphragmatic dysfunction canlead to a cascade of signaling events, which affect the brain and otherorgans. As both vagus and phrenic nerves innervate the diaphragm muscle,stimulation of either the vagus or phrenic nerve can affect a signalingcascade in the other. The potential implications of the stimuli on thebrain, other body organs, and tissues will be discussed further below.

Both delirium and cognitive dysfunction occur in as many as 87% of theintensive care unit (ICU) patients when they are provided with pulmonarysupport via invasive MV (Ely E W et al., “Delirium in mechanicallyventilated patients: validity and reliability of the confusionassessment method for the intensive care unit (CAM-ICU),” JAMA, 2001).While treatment methods have progressed, delirium and cognitivedysfunction remain a major problem in MV patients.

Aberrant neuro-signaling may lead to neurological, cellular, andinflammatory processes, which may lead to cognitive impairment duringand after treatment with mechanical ventilation.

A vagotomy in subjects receiving MV may mitigate the increase in thelevels of the dopamine-synthesizing enzyme and the degree of apoptosisin the hippocampus compared to control animals. This implies that thevagus nerve is sending a signal, related to MV, to cause the dopamineincrease.

Critical care patients with a preexisting brain injury (e.g., stroke,TBI, acute ischemia, etc.), who are placed on mechanical ventilation,are at an increased risk for long term cognitive defects. Thus, there isa need for preventative or neuroprotective therapy that is efficaciousin humans.

Inflammation is a common pathomechanism of acute lung injury and acutebrain injury, affecting brain homeostasis. The inflammatory cascadefollowing an acute brain injury may adversely affect the lungs, butevidence indicates that the opposite can occur as well. This can occurby means of a complex interaction between the autonomic,neuro-inflammatory, neuroendocrine, and immunologic pathways, which arephysiologically programmed to preserve systemic homeostasis, but incertain circumstances may be responsible for harmful effects on remoteorgans and systems.

The lungs sense mechanical stimuli via mechanoreceptors, and theinformation is communicated to the brain via the autonomic nervoussystem. The afferent vagal nerves communicate information from pulmonarystretch receptors to the respiratory center in the brain. To date, thereremains a need for effective treatments to help treat or mitigate bothbrain and lung injuries.

Afferent and efferent vagus nerves, α7 nAChR-expressing inflammatorycells, and central vagal nucleus in the brain form an inflammatoryreflex that may control inflammation and immunity. Sensory neuronsdetect pathogens, damage, or injury via peripheral afferent vagal nerveendings and may then provide feedback to nucleus tractus solitarii (NTS)in the brain stem. The information is processed, and the efferent vagusnerve may transmit integrated information by action potentials to theceliac ganglion and then to other parts of the body.

The vagus nerve originates from medullar oblongata, which consists offour nuclei: dorsal nucleus, nucleus ambiguous, NTS, and spinal nucleusof trigeminal nerve. Approximately 80% of afferent sensory fibers arecontained in the vagus nerve and are responsible for transmission of theinformation to the NTS. There are numerous afferent vagus nerve endingsin the lungs and diaphragm. For example, lung information is transmittedvia the afferent arm to NTS, a processing center, which is capable ofdifferentiating types of infection, inflammation, or injury. The vagalnerve endings may synthesize and release Ach, which in turn activates α7nAChR in the pro-inflammatory cells such as macrophages and neutrophilsor epithelial cells to regulate the production of pro-inflammatorycytokines via NF-κB.

One mechanism for the transient ischemia protection involves theafferent vagal pathway. The vagus nerve consists of both afferent andefferent fibers with 80% of the afferent impulses originating in thethoracic and abdominal organs. The afferent activity is relayed to theNTS, which has projections to the locus coeruleus (LC) which controlsthe release of norepinephrine (NE) and 5-hydroxytryptamine (5-HT). NEactivated by VNS may have anti-inflammatory effects and may stimulatethe release of 5-HT. Data showing that agonists of 5-HT may reduce therelease of glutamate in cerebral ischemia indicating the 5-HT attenuatesexcitotoxicity by inhibiting glutamate release. These afferent nervepathway effects could contribute to the effectiveness of NVS in brainischemia. Alternatively, the efferent vagal pathway may also induceneuroprotection via the cholinergic anti-inflammatory pathway (CAP)which is activated by the central cholinergic system in the brain viathe efferent fiber of the vagus nerve.

Electrical stimulation of the vagus nerve leading to the activation ofthe CAP may suppress brain inflammation, leading to neuroprotection inischemic stroke. The efferent vagus nerve stimulation can also inhibit alocalized inflammatory cytokine cascade in tissues and organs that areserved by efferent vagus nerve fibers.

When activated, the resident macrophages of the central nervous system(CNS), the microglia, may secrete molecules that cause neuronaldysfunction, or degeneration. It has further been discovered thatstimulation of efferent vagus nerve fibers releases sufficientacetylcholine to mitigate a systemic inflammatory cytokine cascade, asoccurs in endotoxic shock, or a localized inflammatory cytokine cascade.

Vagus nerve stimulation may cause up-regulation (expression) of α7nAChR. The cellular and molecular mechanism for anti-inflammation may bepartly attributable to acetylcholine (Ach), a neurotransmitter mainlyreleased from vagus nerve endings. Activation of α7 nAChR by Ach onmacrophages may suppress the release of pro-inflammatory cytokines inperipheral circulation, thereby preventing tissue damage via theinflammation reflex of the VN. The α7 nAChR receptors are commonlyexpressed in the brain including neurons glia and endothelial cells.Activation of these receptors may enhance neuronal resistance toischemic or other types of insults.

An alternate technique to stimulate neural tissue, without the need forinvasive procedures, is temporally interfering stimulation and involvescrossing two high frequency electrical signals at the specific brainregion to be stimulated. The two signals interfere with each other,resulting in a low frequency signal at the target area. Low frequencysignals may provoke neurons to fire, while high frequency signals donot, so the targeted area may be activated while the surrounding tissueis not.

SUMMARY

Embodiments of the present disclosure relate to, among other things,systems, devices, and methods for preventing, moderating, and/ortreating brain injury. Each of the embodiments disclosed herein mayinclude one or more of the features described in connection with any ofthe other disclosed embodiments.

This disclosure includes methods for treating a subject. In someaspects, the methods may include obtaining a test result reflecting acondition of a brain in the subject; determining a stimulation parameterbased on the test result; and stimulating a nerve based on thestimulation parameter, wherein stimulation of the nerve assists orcauses contraction of a respiratory muscle in the subject. In someexamples, the nerve may be a phrenic nerve, and the respiratory musclemay be a diaphragm muscle.

In some examples, the nerve may be a first nerve, and the methods mayfurther include stimulating a second nerve, wherein stimulation of thesecond nerve initiates a biological response in the brain that reduces alevel of a causing factor of a brain injury. The second nerve may be avagus nerve. The stimulation of the second nerve may affect signalingfrom the second nerve to the brain or a lung in the subject. The methodsmay further include stimulating a third nerve. In these cases, thesecond nerve may be a left vagus nerve, and the third nerve may be aright vagus nerve. In some cases, the nerve may be a first nerve, andthe methods may further include inhibiting transmission of an aberrantsignal by a second nerve.

In some examples, the second nerve may be stimulated by a nervestimulator. For example, the second nerve may be stimulated by anexternal nerve stimulator. The external nerve stimulator may bepositioned on a skin area adjacent to a vagus nerve in the subject.Alternatively or additionally, the second nerve may be stimulated by animplantable nerve stimulator. The second nerve may be stimulated bymanual, mechanical, electrical, ultrasonic, or electromagnetic energy.

In some examples, the test result may be from imaging the brain.Alternatively or additionally, the test result may comprise a level ofan inflammation- or pain-related protein in blood of the subject. Themethods may further include performing a test that provides the testresult.

In some examples, stimulating the nerve may include inserting a catheterwith one or more electrodes in a blood vessel of the subject, andpositioning the one or more electrodes proximate the nerve.

In some examples, the methods may further include ventilating thesubject with a mechanical ventilator. In such cases, the test result maycomprise an effect of ventilation on the brain. The methods may furtherinclude stimulating a second nerve during at least a portion of aventilation inspiration period.

In some aspects, the methods of treating a subject may includestimulating a first nerve with a first stimulator to assist or causecontraction of a respiratory muscle in the subject; and stimulating asecond nerve with the first stimulator or a second stimulator to reducea level of a causing factor of a brain injury. The methods may furtherinclude stimulating a third nerve with the first stimulator, the secondstimulator, or a third stimulator to assist or cause contraction of therespiratory muscle in the subject. The causing factor of the braininjury may be inflammation in the brain. The first nerve may be aphrenic nerve, and the second nerve may be a vagus nerve. Therespiratory muscle may be a diaphragm muscle.

In some examples, the stimulation of the first nerve may be in synchronywith stimulation of the third nerve. Alternatively or additionally, thestimulation of the first nerve may be coordinated with stimulation ofthe second nerve. The stimulation the first nerve may be in synchronywith stimulation of the second nerve.

In some examples, the methods may further include ventilating thesubject with a mechanical ventilator. The second nerve may be stimulatedduring at least a portion of a ventilation inspiration period.

In some example, the stimulation of the second nerve may be performedwhile the first nerve is not stimulated by the first stimulator. Thefirst stimulator may comprise an intravascular catheter having a set ofelectrodes configured to stimulate a phrenic nerve. The secondstimulator may comprise an intravascular catheter having a set ofelectrodes configured to stimulate a vagus nerve.

In some aspects, the methods for treating a subject may includestimulating a first nerve with a stimulator to assist or causecontraction of a respiratory muscle in the subject; obtaining a testresult of a vagus nerve activity in the subject; generating astimulation parameter based on test result; and stimulating at least oneof the first nerve and a second nerve based on the stimulationparameter. The second nerve may be a vagus nerve, and stimulating atleast one of the first nerve and the second nerve based on thestimulation parameter may include stimulating the second nerve based onthe stimulation parameter. The first nerve may be a first phrenic nerve,and the second nerve may be a second phrenic nerve. In some cases, thetest result may be obtained by testing heart blood flow, testingperipheral blood flow, testing blood pressure, imaging, or assessinginflammation- or pain-related molecules in blood of the subject.

The disclosure also includes systems. In some aspects, the systems mayinclude a processor configured to: receive a test result reflecting acondition of a brain in a subject; and determine a stimulation parameterbased on the test result; and a stimulator configured to stimulate anerve based on the stimulation parameter, wherein stimulation of thenerve assists or causes contraction of a respiratory muscle in thesubject. The systems may further include a mechanical ventilator. Thesystems may further include one or more switches operatively connectedto the processor, the one or more switches being configured to regulatestimulation output to the stimulator.

In some examples, the systems may further include a sensor configured todetect a cardiac event, a respiratory event, a catheter location, ablood pressure, or a level of an inflammatory agent. The stimulator maybe in communication with the sensor. The stimulator may comprise anintravascular catheter having a first set of electrodes configured tostimulate a right phrenic nerve and a second set of electrodesconfigured to stimulate a left phrenic nerve. The stimulator may beconfigured to affect signaling of a phrenic nerve, signaling of a vagusnerve, or a combination thereof.

In some aspects, the systems may include an electrode configured tostimulate a first nerve to assist or cause contraction of a respiratorymuscle in the subject; and a stimulator configured to stimulate a secondnerve to reduce a level of a causing factor of a brain injury. Thestimulator may comprise an intravascular catheter having one or oreelectrodes configured to stimulate a vagus nerve. The systems mayfurther include a catheter configured for intravascular insertion,wherein the catheter comprises a first plurality of electrodes and asecond plurality of electrodes.

In some aspects, the systems may include a first nerve stimulatorconfigured to stimulate a first nerve, wherein stimulation of the firstnerve assists or causes contraction of a respiratory muscle in thesubject; and a processor configured to: receive a test result of a vagusnerve activity in the subject, and generate a stimulation parameterbased on the test result; and a second nerve stimulator configured tostimulate a second nerve based on the stimulation parameter.

BRIEF DESCRIPTION OF DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate non-limiting embodiments of thepresent disclosure and together with the description serve to explainthe principles of the disclosure.

FIG. 1 illustrates the anatomy of selected nerves, tissues, and bloodvessels in a person's neck, brain, lungs, and upper torso.

FIG. 2 illustrates the anatomy of selected nerves and blood vessels in aperson's neck and upper torso, the diaphragm and intercostal respiratorymuscles, an exemplary stimulation device (e.g. catheter) placed in onevein, a control unit, a sensor (e.g., motion sensor, airflow sensor,and/or pressure sensor), an exemplary remote control device, a graphicaluser interface, a pulse generator, and an external respiratory supportdevice, according to an exemplary embodiment.

FIG. 3 illustrates the anatomy of selected nerves and blood vessels in aperson's neck and upper torso, along with a first exemplary stimulationdevice (e.g. catheter) placed in a first location (e.g. vein, artery,skin, etc.) and a second exemplary stimulation device (e.g. catheter)placed in a second location (e.g. vein, artery, skin, etc.), in additionto a control unit.

FIG. 4A illustrates a ventral view of a pair of exemplary cathetershaving windows that may align with nerve-stimulating electrodes withinthe catheter, with the exemplary catheters inserted in a person's neckand upper torso, according to an exemplary embodiment.

FIG. 4B illustrates a ventral view of a single exemplary catheter withlocation securement means (e.g. anchor, adhesive, expandable coil/helix,etc.), the catheter having windows that may align with nerve-stimulatingelectrodes within the catheter, with the exemplary catheter inserted ina person's neck and upper torso, according to an exemplary embodiment.

FIG. 5 illustrates a perspective view of an exemplary catheter withconductors and electrodes exposed on an exterior of the catheter andincluding fluid transport lumens, according to an exemplary embodiment.

FIG. 6 illustrates an exemplary stimulation catheter with flexibleelectrical leads, circuits, and electrodes.

FIG. 7 illustrates the anatomy of selected nerves and blood vessels in aperson's neck and upper torso along with an exemplary implantedstimulation device (e.g. catheter and pulse generator), a controlbutton, and a control unit connected via a wireless connection,according to an exemplary embodiment.

FIG. 8 illustrates the anatomy of respiratory muscles of the torso, atransdermal respiratory muscle stimulation array of electrodes placedupon the skin of the patient over the intercostal muscles,transesophageal stimulation electrodes, and an external respiratorysupport device, according to an exemplary embodiment.

FIG. 9 illustrates a block diagram of a nerve stimulation system havingan intravascular catheter and a control unit, according to an exemplaryembodiment.

DETAILED DESCRIPTION

Throughout the following description, specific details are set forth toprovide a more thorough understanding to persons skilled in the art. Thefollowing description of examples of the technology is not intended tobe exhaustive or to limit the system to the precise forms of any exampleembodiment. Accordingly, the description and drawings are to be regardedin an illustrative, rather than a restrictive, sense.

Further aspects of the disclosures and features of example embodimentsare illustrated in the appended drawings and/or described in the text ofthis specification and/or described in the accompanying claims. It maybe understood that both the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of the invention, as claimed. As used herein, theterms “comprises,” “comprising,” “including,” “having,” or othervariations thereof, are intended to cover a non-exclusive inclusion suchthat a process, method, article, or apparatus that comprises a list ofelements does not include only those elements, but may include otherelements not expressly listed or inherent to such a process, method,article, or apparatus. Additionally, the term “exemplary” is used hereinin the sense of “example,” rather than “ideal.” As used herein, theterms “about,” “substantially,” and “approximately,” indicate a range ofvalues within +/−15% of a stated value.

Reference will now be made in detail to examples of the presentdisclosure described above and illustrated in the accompanying drawings.Wherever possible, the same reference numbers will be used throughoutthe drawings to refer to the same or like parts.

The terms “proximal” and “distal” are used herein to refer to therelative positions of the components of an exemplary medical device orinsertion device. When used herein, “proximal” refers to a positionrelatively closer to the exterior of the body or closer to an operatorusing the medical device or insertion device. In contrast, “distal”refers to a position relatively further away from the operator using themedical device or insertion device, or closer to the interior of thebody.

In general, embodiments of this disclosure relate to systems, medicaldevices, and methods for electrically stimulating a patient's nerves,and preventing, modulating, controlling, or treating injury (e.g.,injury of the brain, the lungs, or the diaphragm muscle). For example,the injury may be caused or enhanced by mechanical ventilation. As usedherein, the term “injury” may refer to an alteration in cellular ormolecular integrity, activity, level, robustness, state, or otheralteration that is traceable to an event. For example, brain injury maybe neuronal injury resulting from stress (repetitive stress),inflammation, oxidative stress, disease, pain, stroke, and/or physicalinjury such as surgery or trauma.

The methods herein may include stimulating one or more nerves, such asone or more phrenic nerves and/or one or more vagus nerves. For example,the methods may include stimulating one or more respiratory muscles(e.g., diaphragm muscle) or a portion thereof by stimulating one or morenerves (e.g., phrenic nerves). Stimulation of one or more phrenic nervesmay play a role in preventing or treating brain injury (e.g., caused bymechanical ventilation). For example, in patients receiving mechanicalventilation, stimulation of phrenic nerves may pace the diaphragm muscleso that the pressure and time required from the mechanical ventilationare reduced. Alternatively or additionally, stimulation of phrenicnerves may initiate a response in the brain to reduce a causing factorof brain injury, such as inflammation. Stimulation of one or more vagusnerves may also initiate a response in the brain to reduce a causingfactor of brain injury, such as inflammation. In some cases, the methodmay include blocking one or more vagus nerves so that the vagus nerve(s)does not transmit aberrant signals (e.g., signals that triggerinflammation in the brain) to the brain. The aberrant signals may resultfrom mechanical ventilation.

The methods may further include monitoring, sensing, and/or testing oneor more functions, activity, or other parameters of the brain, obtainingthe results of the sensing or tests, and analyzing these results, forexample, to determine the effect of the nerve stimulation and/ormechanical ventilation on brain function and/or activity. Based on thetest results and their analysis, parameters (e.g., timing, duration, andprofile such as intensity) for nerve stimulation may be generated ormodified, and stimulation of nerves may be initiated or modified basedon the parameters. Exemplary tests on brain function include magneticresonance imaging (MRI) such as functional MRI, a computed tomography(CAT) scan, a positron emission tomography (PET) scan, amagnetoencephalography (MEG) scan, any other imaging or scanningmodality, an electroencephalogram (EEG) test, detection of a cardiacevent and/or a respiratory event, and/or measurement of blood pressure,intracranial pressure, cardiopulmonary pressure, brain oxygenation, andpartial pressure of carbon dioxide in arterial blood (PaCO₂). Brainoxygenation may be monitored in several ways including via jugularvenous saturation, near-infrared spectroscopy, and/or microdialysiscatheter assessment. Tests on brain function may also include laboratorytests of one or more bodily fluids (e.g., blood, urine, fluidsurrounding the brain, etc.), or one or more tissues. The laboratorytests may detect levels of molecules (e.g., cytokines) indicative ofbrain injury or dysfunction, such as inflammation. Tests on brainfunction may further include neurological examinations (e.g., assessingof motor or sensory skills, like testing reflexes, eye movements,walking, and balance), and tissue biopsy. The tests may further includecognitive assessment (e.g., assessing mental status) by asking patientsto conduct specific tasks and answer several questions, such as namingtoday's date or following a written instruction.

Alternatively or additionally, the methods may include testing thestatus of one or more nerve (e.g., vagus nerve) stimulations. In somecases, the methods may include testing brain function and the status ofone or more nerve stimulations. Exemplary tests on the status of nerve(e.g., vagus nerve) stimulations include detection of electrodermalactivity, heart rate variability, responses related to the control ofpupil diameter and blood flow to the eye, peripheral blood flow (e.g.,measured with laser Doppler flow meters), heart rate and blood pressurevariability analysis, valsalva maneuver, deep metronomic breathing, asustained handgrip test, a cold pressor test, a cold face test, activeand passive orthostatic challenge maneuvers, blood pressure response toa mental arithmetic test, pharmacological baroreflex testing, athermoregulatory sweat test, a quantitative sudomotor axon reflex test,magnetic resonance imaging (MRI), single-photon emission computedtomography (SPECT), evaluation of electroencephalography (EEG)waveforms, the measurement of visual, audio and somatosensory evokedpotentials, changes in absolute vital sign values, and changes in painthreshold. The tests may also include detecting chemistry (e.g., levelsand activities of proteins or other molecules such as inflammation- orpain-related molecules) in the blood or other bodily fluids. Thechemistry tests may include measuring the level and/concentrations ofTNF-α, other cytokines, serotonin, gastrin, and/or norepinephrine.

The tests on brain function and/or vagus nerve stimulation may beperformed prior to, during, or after ventilation or at different stagesof ventilation. For example, the tests may be performed before, during,or after an inflation stage of mechanical ventilation. Alternatively oradditionally, the tests may be performed before, during, or afterstimulation of a nerve. Brain function and/or vagus nerve stimulationstatus or activity may be determined based on the test results.Alternatively or additionally, the results from the tests performed atdifferent times may be compared to each other or to reference thresholdvalues or ranges, e.g. thresholds or ranges that indicate normal brainfunction or other levels of brain function. In such cases, brainfunction and/or vagus nerve stimulation status may be determined basedon the comparisons.

For a patient receiving or having received a nerve stimulation therapy,the brain function and/or vagus nerve stimulation status in the patientmay be detected and compared to parameters indicative of normal functionand/or status of the brain and/or the nerves. If a difference isdetermined, one or more parameters of nerve stimulation may be modifiedto adjust the nerve stimulation therapy administered to the patient. Theadjustment may be performed continuously (e.g., based on real-timemonitoring of brain function and/or vagus nerve stimulation status) fordelivering optimal and personalized therapy to the patient.

In some cases, the methods may further include administering one or moredrugs to the subject during the nerve stimulation, pacing, and/orventilation procedure described herein. In embodiments, the drug therapymay be based on the analysis of any of the tests described above. Insome cases, the one or more drugs may include those associated withdecreased time to extubation and helpful in reducing brain injury. Forexample, the one or more drugs may include propofol and/ordexmedetomidine. In some cases, the one or more drugs may include thoseaffecting smooth muscle tension and/or capable of reducingtrachea-bronchial tone/tension. Such drugs may also help reducepulmonary stretch receptor-induced aberrant vagus signaling responsiblefor brain injury.

The systems herein may include medical devices for performing themethods described in the disclosure. The medical device may includecomponents such as a catheter having a tubular member and one or moreelectrode assemblies, a signal generator to provide stimulation energyto the electrode assemblies, one or more sensors to sense the conditionof the patient and adjust the stimulation signals, and one or morecontrol components allowing a user (e.g., a physician or a patient) toadjust the parameters of nerve stimulation. The different embodiments ofthe various medical device components may be combined and used togetherin any logical arrangement. Furthermore, individual features or elementsof any described embodiment may be combined with or used in connectionwith the individual features or elements of other embodiments. Thevarious embodiments may further be used in different contexts than thosespecifically described herein. For example, the disclosed electrodestructures may be combined or used in combination with variousdeployment systems known in the art for various diagnostic and/ortherapeutic applications.

The systems and methods disclosed in this disclosure may help to achieveat least one or more of the following to a patient: preventing,modulating, controlling, or treating brain injury, preventing,modulating, controlling, or treating lung injury, activating thediaphragm muscle (e.g., by stimulating phrenic nerves), or providingrespiratory support or mechanical ventilation.

In some embodiments, the systems and methods herein may reduce andprevent brain injury (e.g., in patients receiving or have receivedmechanical ventilation) via phrenic or diaphragm stimulation. Electricalstimulation of at least one phrenic nerve and/or hemi-diaphragm duringmechanical ventilation may provide effective O₂/CO₂ gas exchange whilereducing upper lung barotrauma (stretch injury) and reducing atelectasis(lung collapse injury). Reducing lung injury may reduce the stimulusthat leads to a cascade of events linked to brain inflammation andcognitive dysfunction. Electrical stimulation of one or more phrenicnerves or diaphragm muscle may result in stabilizing the afferentsignaling to the brain to mitigate aberrant vagal signaling implicatedin brain cell death. The diaphragm muscle activation by phrenic or othernerve/muscle stimulation may provide improved or stabilizing sensoryinput to brain receptors, compared to those sent during mechanicalventilation alone (e.g. thereby replacing the input typically receivedby the brain, as non-limiting examples from phrenic, vagus, or pulmonarystretch receptor signaling, during brain-driven diaphragm activation).The period of stimulation may vary since biological structures mayprefer slight variation. The stimulation (e.g. phrenic, vagus, muscle,etc.) may be provided by a transvascular (e.g., transvenous) catheter,cuff electrodes, implanted electrodes, transcutaneous stimulators, orother suitable methods. For example, stimulation of vagus nerves may beprovided by an external nerve stimulator, e.g., a stimulator positionedon a skin area adjacent to a vagus nerve. Alternatively or additionally,stimulation of vagus nerves may be provided by an implantable nervestimulator.

In some embodiments, the systems and methods herein may reduce braininjury via vagus nerve block coordinated with mechanicalventilation-delivered breath. Electrical stimulation may be used toblock the aberrant pain signals, e.g., by using a kilohertz frequencynerve block via vagus nerves, which may reduce inactivation of Akt(protein kinase B) and help mitigate cell death. Kilohertz frequencyelectrical stimulation could be delivered (e.g. at or about 40 kHz, orwithin a range of [1 kHz-100 kHz]) via electrodes placed on or near thevagus nerve (e.g., including a branch of the vagus nerve) to temporarilyblock afferent signals. The blocking signal may be designed to occur insynchrony with a specific phase (e.g., inspiration) of the mechanicallydelivered breath to minimize aberrant signaling. The blocking signal maybe designed such that its intensity is modulated by one or morecharacteristics of the mechanical ventilation delivered breath (e.g.,pressure, flow, tidal volume). The vagus-blocking signal may bedelivered via transcutaneous electrodes, minimally invasively placedelectrodes, transvenous electrodes, subcutaneous electrodes, directcontact electrodes, or other suitable delivery vehicle. The stimulationprofile envelope of the blocking signal may be tailored to minimize thepassage of the aberrant vagus signaling to the brain caused, forexample, by the pulmonary stretch pain receptors. In one embodiment, thesystems may include a sensor for adjusting the timing, duration, andprofile of the nerve block signal to optimize the blockade of theaberrant signal. Sensors or other inputs may be used to trigger theblocking signal. For example, in one embodiment, the detection ofbreaths (e.g. coming from the mechanical ventilator) may be used tocoordinate/synchronize stimulation of the phrenic nerve(s) and/orstimulation of the vagus nerve(s) with the mechanical ventilator. Onesuch sensor includes a mechanical transducer placed on the patient'sneck or throat (e.g. a microphone) that can detect the “pink noise” inthe throat or endotracheal tube whenever a breath occurs. Alternatively,in another embodiment, a transducer may be attached in the airflowcircuit (e.g. the inspiratory limb, where the inspiratory phase of thebreath could be detected) or inserted or attached to a portion of theairflow circuit tubing. This may be used with an invasive or anon-invasive mechanical ventilator. In yet another embodiment, amechanical transducer on a portion of the airflow circuit (e.g. a straingauge) may serve as a stretch-detector that is clipped or wrapped aroundthe tubing (either the inspiratory limb, or the tube that connects thewye-piece to the endotracheal tube). Changes in pressure associated withthe breathing cycle may be detected by the mechanical transducer tosynchronize stimulation.

In some embodiments, methods and systems herein may reduce diaphragm,lung, and brain injury via phrenic stimulation, and vagus nerve blockcoordinated with MV delivered breath. Stimulating at least one phrenicnerve may activate the diaphragm, which may stabilize aberrant signalssent to the brain via afferent neuro pathways, mitigating diaphragmatrophy, and reducing lung injury. The activation of diaphragm may alsoinclude stimulating at least one vagus nerve to block a signal. In oneaspect, both left and right phrenic and vagus nerves may be stimulated.These stimulation signals may be delivered by one or more devices. Asingle catheter placed via the left (Internal Jugular) IJ or (ExternalJugular) EJ may stimulate the left vagus, left phrenic, and rightphrenic nerve. In one aspect, an electrode population for sending theleft vagus nerve block may be located proximal to the other electrodepopulations. In such an embodiment, the block may not prevent the distalphrenic signals from reaching the diaphragm muscle. The therapies mayalso be delivered by two or more separate devices. For example, anintravenous catheter placed in the jugular vein (internal or external)or subclavian vein may be used in combination with an external vagusstimulation device mounted on a neck collar, skin mounted transcutaneousdevice, or a set of electrodes placed percutaneously. The vagus nerveblock may be timed to occur with the delivery of the mechanicalventilation breath, or with delivery of the phrenic nerve stimulation. Avariety of sensors may be used to coordinate the stimulation with apatient's breathing or with the delivery of a breath from the mechanicalventilator. Sensors may sense heart rate, CO₂, O₂, breathing,temperature, motion, impedance, electromyography, electrocardiography,airflow, pressure, or any combination thereof.

In some embodiments, the methods and systems herein may reduce diaphragminjury, lung injury, and/or brain injury via phrenic stimulation, and/orvagus stimulation, and in some cases vagus nerve block coordinated withmechanical ventilation delivered breath. Electrical stimulation may alsobe used to deliver anti-inflammatory signaling via the vagus nerve. Lowduty cycle signaling may be effective in providing long-term cerebralprotection. In one embodiment, positive vagus pulse trains may be sentin between phrenic stimulation pulses. Alternatively or additionally,blocking pulses to the vagus nerve may be sent between positivestimulation pulses to the vagus nerve, or at the same time, or withportions of overlap. For example, positive (passivating) signals may besent to the brain via the vagus nerve during the time between breaths,and the nerve block on the vagus nerve may be established when themechanical ventilator is stretching the lungs to block the pain signalfrom reaching the brain. The blocking signal may be designed such thatits intensity is modulated by one or more characteristics of themechanical ventilation delivered breath (e.g., pressure, flow, tidalvolume, etc.). The positive signal to the vagus may be designed suchthat its intensity is modulated by one or more characteristics of themechanical ventilation delivered breath (e.g., inversely proportional topressure, flow, tidal volume, etc.). In some cases, vagus nervestimulation immediately after an ischemic event may be neuroprotective.For example, a patient may receive a pulse train delivered to a vagusnerve after a cerebral ischemic event. The pulse train may beinterrupted to establish a nerve block when the ventilator is inflatingthe lungs, then the positive signal may be re-initiated between breaths.Alternatively or additionally, the positive signal may be sentcontinuously and it may be blocked by high frequency nerve block (e.g.,every few seconds). In some cases, the positive signal does not have tobeen sent all the time or for long periods of time. For example, thepositive signal may be sent once every few hours, or once a day.

Vagus stimulation may be transvascular, transdermal, or via minimallyinvasive electrodes placed in the proximity of the vagus nerve.Techniques may include selectively activating and/or blocking efferentand afferent neural pathways. This may involve simultaneous afferentvagus blocking and efferent phrenic stimulation. Another aspect includesa vagus stimulation device that delivers a nerve block during theinspiration phase of mechanical ventilation and then ananti-inflammatory stimulation signal to the vagus nerve at other timeperiods (e.g., a jugular catheter for vagus stimulation thatsynchronizes with the mechanical ventilation or with the phrenic nervestimulation signal, delivering high frequency block when stretchreceptors are activated and delivering anti-inflammation inducingsignals other times).

In some embodiments, the methods and systems herein may reduce braininjury via phrenic pacing in mechanical ventilation patients. Aspects ofthe present disclosure may include systems and methods for reducing peakventilator pressure, limiting end-inspiratory lung stretch to provideadequate ventilation while reducing lung inflammation, and reducingatelectrauma.

In some embodiments, the methods and systems herein may reduce braininjury by reducing the positive pressure required from externalrespiratory support and counteracting the effects of aberrant vagalsignaling. Multiple means may be used to reduce the positive pressure,including iron lung, extracorporeal membrane oxygenation (ECMO), as wellas phrenic nerve and respiratory muscle (e.g. diaphragm, intercostal,etc.) stimulation. Aberrant vagal signaling may be mitigated by anymethod used to reduce pulmonary stretch receptor activation as well aswith vagus/phrenic stimulation or nerve block.

FIG. 1 illustrates the anatomy of the neck and chest and, in particular,the relative locations of the left and right phrenic nerves (PhN), vagusnerves (VN), internal jugular veins (IN), brachiocephalic veins (BCV),subclavian veins (SCV) and superior vena cava (SVC). The PhNs runapproximately perpendicular to and close to the BCVs in areas 107R and107L near the IN/BCV junctions. Each PhN may have more than one branch.The branches may join together at variable locations ranging from theneck region to the chest region below the IN/BCV junctions. In thelatter case, branches of the PhN on either side of the body may courseon opposite sides of the BCVs. The right PhN may include branches thatcourse on either side of the SVC. The left and right PhNs extendrespectively to left and right hemi-diaphragms (HD). Upon leaving themedulla oblongata, the VN extends down the neck between the trachea andesophagus, into the chest, abdomen and further, creating an extensiveinformation network with various organs (e.g. lungs, diaphragm, etc.),and other tissues. The right vagus nerve gives rise to the recurrentlaryngeal nerve, which descends into the neck between the trachea andesophagus.

Referring to FIG. 2, the systems described herein may include severalcomponents, including: a stimulator having one or more electrodes orelectrode assemblies, such as a transvascular nerve stimulation catheter12 including stimulation electrodes (e.g., shown FIG. 2) ortranscutaneous stimulation array 13 (FIG. 8); a signal generator 14 toprovide stimulation energy to the electrode assemblies; one or moresensors 16, or means for sensing, to sense a condition of the patientand inform adjustments to the stimulation signals and/or externalrespiratory support; and a control unit 18 to manage the parametersassociated with the delivery of the stimulation signals to theelectrodes. In some embodiments, the system may incorporate a remotecontroller 20, a graphical user interface (GUI) 21, a touchscreen (e.g.,as part of GUI 21), a hand-held controller (e.g., remote controller 20),a keyboard, a computer (e.g., control unit 18), a smart phone, a tablet,or another input device.

In some examples, the stimulator devices (e.g., catheter 12) are readilyapplied to, or inserted into, the patient, temporary, and easily removedfrom the patient without the need for surgery at a later time. Thestimulator, such as catheter 12 or other stimulation array, may bepositioned internal to the patient via a percutaneous incision in thepatient's neck. In some cases, the stimulator may be inserted proximatesubclavian, femoral, or radial regions of the patient. In otherexamples, as described herein, the stimulator may be positioned externalto the patient.

The various system components described herein may be combined and usedtogether in any logical arrangement. Furthermore, individual features orelements of any described example may be combined with or used inconnection with the individual features or elements of otherembodiments. The various examples may further be used in differentcontexts than those specifically described herein. For example, thedisclosed electrode structures may be combined or used in combinationwith various deployment systems known in the art for various diagnosticand/or therapeutic applications.

FIG. 2 further illustrates the anatomy of the neck and chest and, inparticular, the relative locations of the left and right phrenic nerves(L. PhN 26 and R. PhN 28), vagus nerves (L. VN 7 and R. VN 9), left andright internal jugular veins (L. IJV 32 and R. IJV 33), left and rightbrachiocephalic veins (L. BCV 25 and R. BCV 27), left and rightsubclavian veins (L. SCV 22 and R. SCV 23), the superior vena cava (SVC24), and intercostal nerves (IN 29). FIG. 2 further illustrates adiaphragm 30 and intercostal muscles 39. The phrenic nerves 26, 28 runapproximately perpendicular to and close to the subclavian veins 22, 23,or in some cases brachiocephalic veins 25, 27 near the junctions of theinternal jugular veins 32, 33 and the brachiocephalic veins 25, 27. Eachphrenic nerve 26, 28 may have more than one branch. The branches mayjoin together at variable locations ranging from the neck region to thechest region below the junctions between the internal jugular veins 32,33 and the brachiocephalic veins 25, 27. In the latter case, branches ofthe phrenic nerves 26, 28 on either side of the body may course onopposite sides of the brachiocephalic veins 25, 27. The right phrenicnerve 28 may include branches that course on either side of the superiorvena cava 24. The left and right phrenic nerves 26, 28 extendrespectively to left and right hem i-diaphragms.

FIG. 2 also illustrates a medical system 100 that includes transvascularnerve stimulation catheter 12 and control unit 18. Catheter 12 mayinclude a plurality of electrodes 34. Catheter 12 may be operablyconnected (e.g., hardwired via cable 5, wireless, etc.) to control unit18. Control unit 18 may be programmed to perform any of the functionsdescribed herein in connection with system 100. In some embodiments,control unit 18 may include a remote controller 20 to allow a patient orhealth professional to control operation of control unit 18 at adistance from the control unit 18. The remote controller 20 may includea handheld device, as illustrated in FIG. 2. In some examples, remotecontroller 20 may include a hand switch, foot switch/pedal, avoice-activated, touch-activated, or pressure-activated switch, a remoteswitch, or any other form of a remote actuator. The control unit 18 mayinclude a touch screen and may be supported by a cart 41.

The remote controller 20 may include buttons 17, 19 that can be pressedby a patient or other user to control breathing patterns. In oneexample, pressing one of buttons 17, 19 can initiate a “sigh” breath,which may cause a greater volume of air to enter the patient's lungsthan in a previous breath. A sigh breath may result when electrodes 34of catheter 12 are directed to stimulate one or more of the phrenicnerves 26, 28 at a higher level than a normal breath (e.g., astimulation train having a longer duration of stimulation or havingpulses with a higher amplitude, pulse width, or frequency). Higheramplitude stimulation pulses can recruit additional nerve fibers, whichin turn can engage additional muscle fibers to cause stronger and/ordeeper muscle contractions. Extended pulse widths or extended durationsof the stimulation train can deliver stimulation over longer periods oftime to extend the duration of the muscle contractions. In the case ofdiaphragm muscle stimulation, longer pulse widths or extended durationof stimulation (train of pulses) have the potential to help expand thelower lung lobes by providing greater or extended negative pressurearound the outside of the lungs. Such negative pressure has thepotential to help prevent or mitigate a form of low pressure lung injuryknown as atelectasis. The increase in stimulation frequency can resultin a more forceful contraction of the diaphragm 30. The increasedstimulation (e.g., higher amplitude, pulse width, stimulation duration,or frequency) of the one or more phrenic nerves 26, 28 may result in amore forceful contraction of the diaphragm 30, causing the patient toinhale a greater volume of air, thereby providing a greater amount ofoxygen to the patient. Sigh breaths may increase patient comfort.

In other examples, buttons 17, 19 may allow the patient or other user tostart and stop stimulation therapy, or to increase or decreasestimulation parameters, including stimulation charge (amplitude×pulsewidth), frequency of pulses in a stimulation train, or breath rate. LEDindicators or a small LCD screen (not shown) on the remote controller 20or control unit 18 may provide other information to guide or inform theoperator regarding the stimulation parameters, the feedback from thesystem sensors, or the condition of the patient.

Alternatively, a control unit having the functionality of control unit18 can be implanted in the patient, along with catheter 12 asillustrated in FIG. 7. In this example, a remote controller and aprogrammer may communicate with the implanted control unit wirelessly.Each of the programmer, the implanted control unit, and remotecontroller may include a wireless transceiver so that each of the threecomponents can communicate wirelessly with each other. The implantedcontrol unit may include all of the electronics, software, andfunctioning logic necessary to perform the functions described herein.Implanting the control unit may allow catheter 12 to function as apermanent breathing pacemaker. A programmer may allow the patient orhealth professional to modify or otherwise program the nerve stimulationor sensing parameters. In some examples, remote controller 20 may beused as described in connection with FIGS. 2, 3 and 8. In otherexamples, remote controller 20 may be in the form of a smartphone,tablet, watch, or other suitable input device.

In yet another additional or alternative example, the control unit ofsystem 100 may be portable. The portable control unit may include all ofthe functionality of control unit 18 of FIG. 2, but it may be carried bya patient or other user to provide the patient with more mobility andmay be disconnected from the cart 41. In addition to carrying theportable control unit, the patient can wear the control unit on a belt,on other articles of clothing, or around his/her neck, for example. Inother examples, the portable control unit may be mounted to a patient'sbed to minimize the footprint of system 100 in the area around thepatient, or to provide portable muscle stimulation in the event abed-ridden patient needs to be transported or moved to another location.

The distal tip of catheter 12 may be a tapered distal end portion ofcatheter 12 and may have a smaller circumference than the body ofcatheter 12. The distal tip may be open at the distal end to allow aguide wire to pass through and distally beyond catheter 12. The distaltip may be softer than other portions of catheter 12, be atraumatic, andhave rounded edges. Catheter 12 also may have one or more ports oropenings in the sidewall of the catheter. A first opening may be locatedat a mid-portion of catheter 12 and other openings may be located near aproximal end of catheter 12. Each opening may be in fluid communicationwith respective lumens in catheter 12, through which fluid can beinfused or extracted. The fluid may exit and/or enter the ports to bedelivered into and/or from a blood vessel.

During use, a proximal portion of catheter 12 may be positioned in leftsubclavian vein 22, and a distal portion of catheter 12 may bepositioned in superior vena cava 24. Positioned in this manner,electrodes 34 on the proximal portion of catheter 12 may be positionedproximate left phrenic nerve 26, and electrodes 34 on the distal portionof catheter 12 may be positioned proximate right phrenic nerve 28. As analternative insertion site, catheter 12 may be inserted into a jugularvein e.g., left jugular vein 32 such as left external jugular vein orleft internal jugular vein or right jugular vein 33 such as rightexternal jugular vein or right internal jugular vein, and superior venacava 24, such that the proximal electrodes are positioned to stimulateleft phrenic nerve 26 and the distal electrodes are positioned tostimulate right phrenic nerve 28.

Left and right phrenic nerves 26, 28 may innervate diaphragm 30.Accordingly, catheter 12 may be positioned to electrically stimulate oneor both of the left and right phrenic nerves 26, 28 to cause contractionof the diaphragm muscle 30 (or a portion thereof) to initiate or supporta patient breath, help reduce the pressure from the mechanicalventilator, open up the lower lungs, reduce lung stretch/injury, and/orreduce aberrant brain signaling which may lead to cognitive injury.

In further examples, catheter 12 can be placed into and advanced throughother vessels providing access to the locations adjacent the targetnerve(s) (e.g., phrenic nerves), such as: the jugular, axillary,cephalic, cardiophrenic, brachial, or radial veins. In addition, thestimulator (e.g., catheter 12 or array 13) may use other forms ofstimulation energy, such as ultrasound, to activate the target nerves.In some examples, the system 100 can target other respiratory muscles(e.g., intercostal) either in addition to, or alternatively to, thediaphragm 30. The energy can be delivered via one or more types ofelectrodes/methods including transvascular electrodes, subcutaneouselectrodes, electrodes configured to be positioned in contact with thenerve (e.g., nerve cuffs), transdermal electrodes/stimulation, or othertechniques known in the field.

The nerve stimulation systems and methods described herein may reduce oreliminate the need for a patient to receive external respiratorysupport. External respiratory support 88 in FIG. 2 can include anydevices or methods to help correct or otherwise enhance blood gasesand/or reduce the work of breathing of a patient. Some non-limitingexamples include mechanical ventilation, non-invasive ventilation (NIV),CPAP, BiPAP, nasal cannula oxygenation, DPS (Synapse, Avery, etc.), andECMO, as described below.

Mechanical ventilation may refer to use of a ventilator to assist orreplace spontaneous breathing. Mechanical ventilation is termed“invasive” if it involves any instrument penetrating through the mouth(such as an endotracheal tube) or the skin (such as a tracheostomytube). There are two main types of mechanical ventilation: positivepressure ventilation, where air (or another gas mix) is forced into thetrachea via positive pressure, and negative pressure ventilation, whereair is drawn into (e.g., sucked into) the lungs (e.g., iron lung, etc.).There are many modes of mechanical ventilation. Mechanical ventilationmay be indicated when the patient's spontaneous ventilation is unable toprovide effective gas exchange in the lungs.

Ventilation also can be provided via a laryngeal mask airway (e.g.,laryngeal mask), which is designed to keep a patient's airway openduring anesthesia or unconsciousness. It is often referred to as a typeof supraglottic airway. A laryngeal mask may include an airway tube thatconnects to an elliptical mask with a cuff, which is inserted throughthe patient's mouth and down the windpipe. Once deployed, the device mayform an airtight seal on top of the glottis (unlike tracheal tubes,which pass through the glottis) to provide a secure or stable airway.

Non-invasive ventilation (NIV) is the use of airway support administeredthrough a face (e.g., oral, nasal, nasal-oral) mask/cannula instead ofan endotracheal tube. Inhaled gases are given with positiveend-expiratory pressure, often with pressure support or with assistcontrol ventilation at a set tidal volume and rate. This type oftreatment is termed “non-invasive” because it is delivered with a maskor other means that is fitted to the face or nose, but without a needfor tracheal intubation. Other forms of non-invasive ventilation includethe use of external negative pressure systems such as is used in aniron-lung. Any device used to reduce the pressure outside the chestcavity or torso of a patient could effectively provide NIV.

Continuous positive airway pressure (CPAP) is a form of positive airwaypressure ventilation, which applies mild air pressure on a continuousbasis to keep the airways continuously open. CPAP may be used forpatients who are able to breathe spontaneously on their own but mayrequire a level of pressure support. It is an alternative to positiveend-expiratory pressure (PEEP). Both modalities stent the lungs' alveoliopen and therefore help recruit more of the lungs' surface area forventilation. PEEP generally refers to devices that impose positivepressure only at the end of an exhalation. CPAP devices apply continuouspositive airway pressure throughout the breathing cycle. Thus, theventilator itself does not cycle during CPAP, no additional pressureabove the level of CPAP is provided, and patients must initiate eachbreath on their own.

Bilevel Positive Airway Pressure (BiPAP) therapy is very similar infunction and design to CPAP. BiPAPs can also be set to include a breathtiming feature that measures the amount of breaths per minute a personshould be taking. If the time between breaths exceeds the set limit, themachine can force the person to breath by temporarily increasing the airpressure. The main difference between BiPAP and CPAP machines is thatBiPAP machines generally have two pressure settings: the prescribedpressure for inhalation (ipap), and a lower pressure for exhalation(epap). The dual settings allow the patient to move more air in and outof their lungs.

Extracorporeal membrane oxygenation (ECMO), which is also known asextracorporeal life support (ECLS), is an extracorporeal technique toprovide prolonged cardiac and respiratory support to patients whoseheart and lungs are unable to provide an adequate amount of gasexchange. The technology for ECMO is similar to that used duringcardiopulmonary bypass, which is typically used to provide shorter-termsupport. During ECMO, blood is removed from the person's body and passedthrough a device, which removes carbon dioxide and provides oxygen tored blood cells. Long-term ECMO patients can often develop respiratorymuscle weakness because of muscle inactivity and other causes. Certaintherapy methods described herein may include delivering stimulationtherapy to a patient receiving both ECMO and another form of externalrespiratory support. Certain therapy methods of this disclosure mayutilize ECMO devices, which include a stimulation array, to deliver thedescribed therapy.

In some examples, catheter 12 can be inserted into (and/or securedrelative to) the patient. In many embodiments, catheter 12 may beremoved from the patient's body when desired without the need forsurgery. For example, catheter 12 of FIG. 3 may be withdrawn once thepatient is breathing independently.

The timing of stimulation of one or more nerves may be coordinated withthe timing of ventilation. For example, a nerve (e.g., a vagus nerve)may be stimulated during at least a portion of a ventilation inspirationperiod.

Alternatively or additionally, timing of stimulation of multiple nervesmay also be coordinated. For example, stimulation of a second nerve isperformed while a first nerve is not stimulated by the one or moreelectrodes of a first plurality of the electrodes of the catheter. Insome cases, stimulating one or more portions of a respiratory muscle(e.g., diaphragm muscle) may be stimulated when a nerve is notstimulated (e.g., when the nerve is blocked, or no stimulation isprovided). In some cases, stimulation output from one or more nervestimulation electrodes may occur in an inverse relationship tostimulation output from the two or more diaphragm stimulationelectrodes. Alternatively or additionally, stimulation output from theone or more nerve stimulation electrodes may occur during stimulationoutput from the two or more diaphragm stimulation electrodes.

FIG. 3 illustrates an exemplary medical system 300 that includes twocatheters (12 and 62), each catheter including one or more lumens andhaving electrodes assemblies (34 and 64) that include proximal electrodeassemblies and distal electrode assemblies. The proximal electrodeassemblies and the distal electrode assemblies of each catheter may eachinclude at least one electrode set or a plurality of electrode sets. Theelectrode assemblies 34 and 64 may be positioned on or within a tubularmember or catheter body of catheter 12 or 62. Catheters 12 and 62 may bepositioned within a patient through the patient's external or internaljugular veins, brachiocephalic veins, superior vena cava, brachial vein(not shown), radial vein (not shown), and/or left subclavian vein. Thecatheters 12 and 62 may be positioned such that at least one of theelectrode sets is directed towards a phrenic nerve, and at least one ofthe electrode sets is directed towards a vagus nerve. For example, thecatheters 12 and 62 may be positioned such that at least one of theelectrode sets is directed towards the left phrenic nerve, at least oneof the electrode sets is directed laterally towards the right phrenicnerve, and at least one of the electrode sets is directed towards avagus nerve. As such, when positioned, catheters may receive signalsfrom a control unit 14 and, using electrodes or the electrode sets,stimulate the left phrenic nerve and/or the right phrenic nerve and/orone or both of the vagus nerves. As shown in FIG. 3, catheter 12 may beconfigured to stimulate the left and the right vagus nerves, andcatheter 62 may be configured to stimulate the right vagus nerve and theright phrenic nerve. Catheters may further include a manifold 36 thatextends external to the patient. Electrical cables and pigtail lumensmay extend from manifold 36. At least one electrical cable 5 or 6 andpigtail lumen may include cable connectors to connect to externalelements, and electrical cables may be coupled to electrical controlunit 14 via a cable connector. The electrical cables may be formed ofelectrical leads that connect to electrode assemblies. Cable connectorsmay be attached (e.g. by solder, crimp, PCB, etc.) to the cables, andone or both of the cable connectors may include a threading.Alternatively or additionally, one or both of cable connectors mayinclude a push-to-pull compression fitting or a slip-lock fitting (notshown). Control unit 14 and other elements may be electronicallyconnected to the components within catheter 12, 62 to both send andreceive signals and/or data to selectively stimulate electrode setsand/or monitor the patient and any response to the stimulation.Alternatively or additionally, the cables may include one or more lumensor fluid lines that connect to one or more internal lumens in catheter12, 62. Additionally the system may contain a push button 17 to triggerthe stimulation or sensing or any other function of the control unit 14.

As shown in FIG. 4A, a subclavian catheter 12 may include two axiallyextending populations of proximal apertures or windows (72 a and 72 b).Each axially extending population includes windows. The electrodes andcorresponding windows may be of any shape (e.g. circular, oval,crescent, oblong, rectuangular, etc.). In one embodiment, a majority ofthe windows within each population are positioned within the same 180degree circumferential position around the exterior of catheter, wherebythe 180 degree circumferential position may differ between the first andsecond electrode populations (e.g. have different axial positions alongthe exterior of catheter). In another embodiment the two populations ofwindows 72 a and 72 b may be substantially longitudinally aligned (e.g.within the same 90 degree circumferential position) and the 90 degreecircumferential position of the first population and the secondpopulation are different, although potentially overlapping. Forinstance, as illustrated in FIG. 4A, one proximal window of a first row72 a is located at the same axial position as a window of a second row72 b, but at a different circumferential position around the exterior ofthe catheter. When positioned in a patient, the two rows of proximalwindows 72 a and 72 b may be substantially posterior facing, and atleast one proximal window may face, abut or be positioned in thevicinity of the left phrenic nerve. The catheter may also include twoaxially extending rows of distal apertures or windows (74 a and 74 b).Again, each axially extending row (74 a, 74 b) includes distal windowspositioned at the same circumferential position around the exterior ofcatheter, but at different axial positions along the exterior ofcatheter. The two rows of distal windows 74 a and 74 b may be unalignedsuch that one distal window of a first row is axially between two distalwindows of a second row. For instance, as illustrated in FIG. 4A, onedistal window of a first row 74 a is located at a different axialposition and at a different circumferential position around the exteriorof the catheter than a window of the second row 74 b. When positioned ina patient, the two rows of distal windows 74 a and 74 b may besubstantially laterally facing (to the patient's right), and at leastone distal window may face, abut, or be positioned in the vicinity ofthe right phrenic nerve. In the example shown in FIG. 4A, when viewedventrally, two unaligned rows (74 a, 74 b) of three distal windows mayappear as one row of six distal windows, because one row is anteriorfacing and one row is posterior facing.

As shown in FIG. 4A, a separate jugular catheter 62 may be inserted ineither left jugular veins or right jugular veins. The jugular cathetermay include a population of apertures or windows 66 such that whenpositioned in a patient, at least one window may face, abut, or bepositioned in the vicinity of the vagus nerve.

Windows on catheters may expose electrodes, allowing for a conductivepath between sets or pairs of electrodes and surrounding tissue,including the blood vessel lumen in which catheter is inserted.Alternatively, electrodes could be printed onto the surface of thecatheter by one of several known means (e.g. conductive inks, polymers,etc.). Further, the electrodes may be integrated into a flexible printedcircuit, which can be attached to, or integrated into, the catheter.Insulation means known in the art would be used to ensure that theelectrodes, and not any unwanted electrical elements, are exposed todirect contact with the patient.

FIG. 4B shows a single catheter 12 placed through a jugular vein intothe superior vena cava. The catheter 12 may include rows of apertures orwindows 86 positioned proximally, medially and distally, such that whencatheter 12 is positioned in a patient, at least one window may face,abut, or be positioned in the vicinity of the left phrenic nerve, atleast one window may face, abut, or be positioned in the vicinity of theright phrenic nerve, and/or at least one window may face, abut, or bepositioned in the vicinity of a vagus nerve. Windows 86 on catheters mayexpose electrodes, allowing for a conductive path between sets or pairsof electrodes and surrounding tissue, including the blood vessel lumenin which catheter is inserted. The catheter 12 may include a feature tosecure or stabilize the catheter within the patient, and or theelectrodes at a specific location. In one embodiment catheter 12 mayhave a helical shape at the distal end or proximal end or both. Thisshape can be formed by heat setting the polymer sheath or tube, or byadding a shaped stainless steel wire or a shape memory nitinol wire orany other shape memory alloy. A shape-memory alloy may activate thehelical shape when heated to a temperate between 30° C. to 45° C., e.g.,37° C. This helical shape may help in adding vessel wall apposition and,in turn, may aid in fixing the catheter in the current location. Thehelical shape may also increase coverage of electrodes in the radialorientation of the blood vessels. This single catheter can be used tostimulate the phrenic nerves (PNs) and or vagus nerves (VNs).

In one example illustrated in FIG. 4B, the distal or proximal portion ofcatheter 12 may be configured to assume a helical shape when positionedwithin the patient to help anchor catheter 12 to the vessel wall or tostabilize catheter 12 during nerve stimulation. The helical shape mayposition electrodes 34 at different radial positions within the vesseland relative to target nerves. Selecting electrodes 34 at differentradial positions within the vessel (whether or not due to any helicalshape), or at different distances from the target neve (whether or notdue to any helical shape), may be useful for nerve stimulation. Forexample, in certain instances it may be desirable to stimulate the nervewith electrodes 34 that are closer to the nerve (e.g., to obtain astronger respiratory muscle response), and in other instances it may bedesirable to stimulate the nerve with electrodes 34 that are fartheraway from the nerve (e.g., to obtain a weaker respiratory muscleresponse, or prevent stimulation of unwanted nerves).

Referring to FIG. 5, catheter 12 may include a stimulation arraycomprising a plurality of electrodes 34 or other energy deliveryelements. In one example, electrodes 34 may be surface electrodeslocated on an outer wall of catheter 12. In another example, electrodes34 may be positioned radially inward relative to the outer wall ofcatheter 12 (e.g., exposed through openings or windows in the outerwall). In yet another example, the electrodes 34 may include printedelectrodes as described in U.S. Pat. No. 9,242,088, which isincorporated by reference herein.

Electrodes 34 may extend partially around the circumference of catheter12. This “partial” electrode configuration may allow electrodes 34 totarget a desired nerve for stimulation, while minimizing application ofelectrical charge to undesired areas of the patient's anatomy (e.g.,other nerves or the heart). As shown in FIG. 5, catheter 12 may includea proximal set 35 of electrodes 34 configured to be positioned proximateto and stimulate left phrenic nerve 26 and a distal set 37 of electrodes34 configured to be positioned proximate to and stimulate right phrenicnerve 28. Electrodes 34 may be arranged in populations extending alongthe length of catheter 12. In one example, proximal set 35 may includetwo rows of electrodes 34 extending parallel to a longitudinal axis ofcatheter 12, and distal set 37 may include two rows of electrodes 34extending parallel to a longitudinal axis of catheter 12.

Furthermore, the catheters described herein may include any features ofthe nerve stimulation devices and sensing devices described in thefollowing documents, which are all incorporated by reference herein intheir entireties: U.S. Pat. No. 8,571,662 (titled “Transvascular NerveStimulation Apparatus and Methods,” issued Oct. 29, 2013); U.S. Pat. No.9,242,088 (titled “Apparatus and Methods for Assisted Breathing byTransvascular Nerve Stimulation,” issued Jan. 26, 2016); U.S. Pat. No.9,333,363 (titled “Systems and Related Methods for Optimization ofMulti-Electrode Nerve Pacing,” issued May 10, 2016); U.S. applicationSer. No. 14/383,285 (titled “Transvascular Nerve Stimulation Apparatusand Methods,” filed Sep. 5, 2014); U.S. application Ser. No. 14/410,022(titled “Transvascular Diaphragm Pacing Systems and Methods of Use,”filed Dec. 19, 2014); U.S. application Ser. No. 15/606,867 (titled“Apparatus And Methods For Assisted Breathing By Transvascular NerveStimulation,” filed May 26, 2017); or U.S. application Ser. No.15/666,989 (titled “Systems And Methods For Intravascular CatheterPositioning and/or Nerve Stimulation,” filed Aug. 2, 2017). In addition,the control units described herein can have any of the functionality ofthe control units described in the above-referenced patent documents(e.g., the control units described herein can implement the methods ofnerve stimulation described in the incorporated documents).

During nerve stimulation, one or more electrodes 34 may be selected fromthe proximal set 35 for stimulation of the left phrenic nerve 26, andone or more electrodes 34 may be selected from the distal set 37 forstimulation of right phrenic nerve 28. Catheter 12 may stimulate nervesusing monopolar, bipolar, or tripolar electrode combinations, or usingany other suitable combination of electrodes 34. In some examples, asecond or third group of electrodes can be used to stimulate otherrespiratory muscles. In general, a stimulator or a stimulation array mayinclude multiple sets of electrodes, with each set being configured tostimulate either the same or different nerves or muscles. When multiplenerves or muscles are being stimulated, the controllers and sensorsdescribed herein may be used to coordinate stimulation to achieve thedesired muscle activation, breath, or level of respiratory support.

As illustrated in FIG. 5, catheter 12 may further include one or morelumens. Each lumen may extend from a proximal end of catheter 12 to adistal end of catheter 12, or to a location proximate the distal end ofcatheter 12. In some examples, lumens may contain or be fluidlyconnected to sensors, such as blood gas sensors, electrical sensors,motion sensors, flow sensors, or pressure sensors. In some examples,catheter 12 may include three lumens (not shown) that may connect withextension lumens 38, 40, 42 that extend proximally from hub 36. Anylumens within catheter 12 may terminate in one or more distal ports 52,50, 48 either at the distal end of catheter 12 or in a sidewall ofcatheter 12. In one example, the lumens may be used to transport fluidto and from the patient, such as to deliver medications or withdrawblood or other bodily fluids, remove CO₂, infuse oxygen, etc. In otherexamples, these lumens may be used to hold a guidewire, stiffening wire,optical fiber camera, sensors, or other medical devices. For example,FIG. 5 illustrates an optical fiber camera 46 inserted into lumen 38,extending through a corresponding internal lumen, and exiting fromdistal port 48. The electrodes 34 may be configured to sensephysiological information from a patient, such as properties of blood,nerve activities, ECG, or electrical impedance.

Catheter 12, or other stimulation devices of this disclosure, mayincorporate markings or other indicators on its exterior to help guidethe positioning and orientation of the device. Catheter 12, or otherstimulation devices of this disclosure, may also include internalindicators (e.g., radiopaque markers, contrast material such as bariumsulfate, echogenic markers, etc.) visible by x-ray, ultrasound or otherimaging technique to assist with positioning the stimulator in thedesired location. Catheter 12 may include any combination of thefeatures described herein. Accordingly, the features of catheter 12 arenot limited to the specific combination shown in FIG. 5.

Referring still to FIG. 5, a hub 36 may be connected to the proximal endof catheter 12. Hub 36 may include a conductive surface and can act as areference electrode during monopolar stimulation or sensing. In someembodiments, hub 36 may be sutured on a patient's skin. In addition, hub36 may be used as an ECG or other reference electrode.

The embodiment illustrated in FIG. 5 incudes a catheter 12 having twentyproximal windows 35 (two rows of ten windows) and eight distal windows37 (two rows of four windows). However, in other embodiments, thecatheter may include fewer or more rows and various numbers of proximalor distal windows. For example, in other embodiments, the catheter mayinclude two, four, eight, ten, twelve, or more proximal windows arrangedin one, two, three, or more rows, and/or two, four, six, ten, twelve ormore distal windows arranged in one, two, three, or more rows. Thenumber of windows may also be an odd number. The windows may be cut(e.g. by a laser, manual skive, drill, punch, etc.) through the exteriorwall of catheter 12, or the windows may be formed by any other suitablemethod, such as during an extrusion process, 3-D printing, or othermanufacturing process. The windows may have a rectangular, oval, square,or any other shape. The windows may be apertures configured to allowelectrical signals to travel from an interior lumen of the catheter tothe exterior of the catheter. Each window may contain an electrode thatis exposed through the window and connected electrically, independentlyof other electrodes to the control unit. U.S. patent application Ser.No. 15/606,867, which is incorporated by reference, discusses suchconnections. In an additional or alternative embodiment, the windows maybe covered by a material that allows electrical signals to pass through.

The dimensions of catheter 12 may be customized in accordance with theanatomy of a particular patient (e.g., different sizes of humans, pigs,chimpanzees, etc.). However, in some embodiments, the length of thesection of the catheter that includes the proximal windows may be 16 cmor less, between 3 and 5 cm, or between 1 and 3 cm. The length of thesection of the catheter that includes the distal windows may be 12 cm orless, between 2 and 4 cm, or between 1 and 2 cm. The distance betweentwo adjacent windows (whether the windows are circumferentially adjacentor longitudinally adjacent on the same row of windows) may be 5 cm orless, 3 cm or less, may be around 1 cm, or may be less than 1 cm. Thesecatheter dimensions are exemplary only, and the catheter may havedimensions that vary from the above ranges and specific measurements.Additionally, catheter 12 may include windows in differentconfigurations than discussed above.

The catheter's distal tip may be a tapered distal end portion ofcatheter 12. The distal tip may be open at the distal end to allow aguide wire to pass through and distally beyond catheter. The distal tipmay have a smaller circumference than the body of catheter, and may besofter than other portions of catheter, atraumatic, and have roundededges.

The catheter may also have a ports 38 a, 40 a, 42 a that are connectedto an individual tube proximally 48, 50, 52 to act as one or moreseparate vascular lines (three as shown in FIG. 5) to help infusedifferent fluids.

FIG. 6 illustrates another example of catheter 12. Catheter 12 shown inFIG. 6 is similar to the catheter of FIG. 5, except that electrodes 34may be formed by conductive inks (such as silver, gold, graphene, orcarbon flakes suspended in polymer or other media) printed on thesurface of catheter 12, as described in U.S. Pat. No. 9,242,088,incorporated by reference herein. These conductive inks may be depositedand adhered directly onto catheter 12 and sealed, except for the exposedelectrodes 34, with outer polyurethane or other flexible insulativefilm/material. The electrodes may be in the form of a flexiblesolid-state circuit that is attached or incorporated into or onto alead, catheter, or another surface. The exposed electrodes 34 may becoated (e.g., with titanium nitride) for purposes such as one or moreof: enhancing electrical properties, such as conductivity and surfacearea; providing corrosion resistance; and reducing the potential forformation of silver oxide, which could be toxic. As shown in FIG. 6, theconductive ink trace of distal electrodes may travel proximally alongcatheter 12 past the more proximal electrodes 34. FIG. 6 furtherillustrates catheter 12 having an ultrasound transducer 54 or othersensor at a distal end of catheter 12.

FIG. 7 illustrates an alternative medical system with similar elementsto the medical system of FIG. 2. This medical system includes a wirelessconnection from control unit 14′ to catheters 12 and a wirelessconnection from a push button or buttons to the control unit 14′. Inthis exemplary system 10, control unit 14′ is implanted in the patient,along with catheter 12. System 10 may further include remote controller16 and a programmer 98 that communicates with control unit 14′wirelessly. In this embodiment, each of programmer 98, control unit 14′,and remote controller 16 may include a wireless transceiver 92, 94, 96,respectively, so that each of the three components can communicatewirelessly with each other. Control unit 14′ may include all of theelectronics, software, and functioning logic necessary to perform thefunctions described herein. Implanting control unit 14′ as shown in FIG.7 may allow catheter 12 to function as a permanent breathing pacemaker.Programmer 98 may allow the patient or health professional to modify orotherwise program the nerve stimulation or sensing parameters. Remotecontroller 16 may be used as described in connection with FIGS. 2 and 3.In other examples, remote controller 16 may be in the form of asmartphone, tablet, watch or other wearable device. Catheter 12 ormultiple catheters may be inserted and positioned as discussed withrespect to FIGS. 2, 3, 4A, and 4B.

Once the catheter is fully inserted into the patient, various electrodesor electrode combinations may be tested to locate nerves of interest andto determine which electrodes most effectively stimulate the nerves ofinterest. For example, in one embodiment, testing may be done to locatethe right phrenic nerve and to determine which group of distalelectrodes in the distal electrode assemblies most effectively stimulatethe right phrenic nerve. Similarly, testing may be done to locate theleft phrenic nerve and to determine which group of proximal electrodesin the proximal electrode assemblies most effectively stimulate the leftphrenic nerve. Similarly, testing may be done to locate the vagus nerveand to determine which group of electrodes in the electrode assembliesmost effectively stimulate the vagus nerve.

This testing and nerve location may be controlled and/or monitored viacontrol unit 14 or 14′, which may include testing programming and/orapplications. For example, control unit 14 or 14′ may test theelectrodes and electrode combinations to determine which combinations(e.g., bipolar, tripolar, quadrupolar, multipolar) of electrodes mosteffectively stimulate the targeted nerve, e.g., the right phrenic nerve,left phrenic nerve, and/or vagus nerve.

As a non-limiting example, testing could involve the use of a signalgenerator to systematically send electrical impulses to selectedelectrodes. By observing the patient's condition or by using sensors(either within or separate from the catheter), the desired stimulationelectrodes may be identified. Electrodes may serve as both stimulatingelectrodes and as sensing electrodes, and the medical system may beintegrated into a mechanical ventilator, which can be used to sense thepatient's condition. Moreover, for example, the control unit may beprogrammed and/or activated to (a) select a first stimulation group ofelectrodes from the electrode assemblies to stimulate the left phrenicnerve, (b) select a second stimulation group of electrodes from theelectrode assemblies to stimulate the right phrenic nerve, (c) select athird stimulation group of electrodes from the electrode assemblies tostimulate the vagus nerve (d) select a first stimulation current for thefirst stimulation group of electrodes to stimulate the left phrenicnerve, (e) select a second stimulation current for the secondstimulation group of electrodes to stimulate the right phrenic nerve,and (f) select a third stimulation current for the third stimulationgroup of electrodes to stimulate the vagus nerve. The selection ofelectrodes and current levels may be pre-programmed or input based onthe patient's characteristics, or the control unit may test differentelectrode groups and current levels and monitor the patient's responseto determine the electrode pairs and current levels.

In some cases, the systems herein may include a transcutaneousnoninvasive vagus nerve stimulator (nVNS) for stimulating a vagus nerveand/or a transcutaneous respiratory muscle stimulator. For example,devices that use electrical current from a small handheld or skinmounted device to stimulate a nerve in the neck or ear lobe may be usedto stimulate a vagus nerve or stimulate nerves/muscles on the torso toactivate a respiratory muscle. Alternatively or additionally, variousother methods may be used to stimulate nerves, such as, for example,subcutaneous electrodes or nerve cuffs connected to the control unit.

When an electrical charge is delivered to the phrenic nerves, thediaphragm muscles may contract and generate negative pressure in thethoracic cavity. The lungs then expand to draw in a volume of air. Thiscontraction of diaphragm muscles can be sensed manually by palpation orby placing a hand on the thoracic cavity, as shown in FIG. 2.Alternatively, the breathing activity can be sensed by placing anairflow or airway pressure sensor in the breathing circuit or placingsensors 16, such as accelerometers or a gyroscope, on the surface of theskin at the thoracic region, as shown in FIG. 2. Sensors 16 can be hardwired to control unit 18 or can be connected using wireless transmittersand receivers.

FIG. 8 illustrates the anatomy of the neck and chest, similar to FIG. 1.FIG. 8 further illustrates an exemplary medical system 200 that includesa transcutaneous electrode array 13. The array 13 includes a series ofelectrodes 44 placed on the surface of the skin of the patient in closeproximity to the intercostal muscles. Electrodes 44 may have anysuitable shape and size, and may serve a variety of functions, such assensing electrical activity and stimulating the muscles or nervesthrough the skin. Electrodes 44 can include stainless steel, conductivecarbon fiber loaded ABS plastic, silver/silver chloride ionic compound,or any other suitable material, or any combination of materials. Eachelectrode 44 can be covered by a polymeric or elastomeric film that mayinclude an adhesive to attach the electrode 44 to skin. Alternatively,the electrode film may contain electrolyte gel for better conduction ofthe signals. In some embodiments, other forms of electrodes, for examplesubcutaneous or needle electrodes, can be used to stimulate intercostalmuscles, or the system may use other forms of stimulation energy, suchas ultrasound, to activate the target nerves or muscles.

FIG. 8 further illustrates a transesophageal tube 46 with electrodes 48on the tube (e.g., integrated on the tube) and/or on an inflatableballoon surrounding all or part of tube 46. Electrodes 48 can be printedon the surface of tube 46 (or the balloon) using conductive ink such assilver ink, gold ink, graphene ink, or carbon-based ink. Alternatively,electrodes 48 can be formed by using an adhesive to secure the electrodematerial, such as platinum iridium, stainless steel, titanium, orsimilar material, to tube 46 and connecting electrodes 48 to controlunit 18 with one or more conductive wires. Electrodes 48 can be used tosense the signals from the phrenic nerves or vagus nerves or some otherneurological element. Electrodes 48 can also be used to stimulate thenerves, such as, for example, at least one of vagus nerves, phrenicnerves, sympathetic ganglia, or the esophageal sphincter.

Alternatively or additionally, system 200 of FIG. 8 can include acatheter with electrodes and/or sensors, as described in the FIG. 2. Torestore negative pressure ventilation, system 200 can stimulate one orboth phrenic nerves to activate the diaphragm muscles, along withstimulating the intercostal muscles (as illustrated via electrodes 44),to create a negative pressure in the thoracic cavity or a compressiveforce to the chest cavity. The system may receive feedback by sensingthe phrenic or vagus activity from one of the electrodes on theintravascular catheter (if used) or transesophageal tube 46. Feedbackfrom nerve activity may be used to determine the stimulation parametersrequired to sustain proper ventilation and whether adjustments to thestimulation parameters are needed. The system can also receive feedbackfrom any other suitable sensor to determine the appropriate stimulationparameters. One or more of each of the following sensors may be includedin either system 100 or system 200: an airflow sensor, an airwaypressure sensor, an accelerometer, a gyroscope, a blood gas sensor, or asensor to detect an inflammatory agent. In some examples, system 100 orsystem 200 may include a sensor to detect an inflammatory agent.Examples of such inflammatory agents include, but are not limited to,erythrocyte sedimentation rate (ESR), cytokines, C-reactive protein(CRP), plasma viscosity (PV), hemoglobin A1C, serum ferritin, red bloodcell width, insulin, nitric oxide, or other biomarkers for aninflammatory disease (e.g., inflammatory bowel disease, Alzheimers,Crohn's Disease, Arthritis, cancers, diabetes).

FIG. 9 illustrates a block diagram of the various components of system.The electrodes, hub, and lumens may be part of catheter describedherein. The catheter may have any number of electrodes and any number oflumens. Five lumens are illustrated in FIG. 9, but in differentexamples, the catheter may include one, two, three, four, or more thanfive lumens. In one example, the catheter may have three lumens (e.g.,extension lumens and corresponding internal lumens), which each may holdone or more of a guidewire or optical fiber camera or may be used forfluid delivery or blood sample extraction. In another example, thecatheter may include four lumens, with one lumen holding or fluidlyconnected to a pressure sensor, one lumen holding or fluidly connectedto a blood gas sensor, and the other two lumens holding a guidewire oroptical fiber camera and/or being used for fluid delivery or bloodsample extraction. It should be understood that any lumen of the systemmay contain or be fluidly connected to any of the devices (e.g.,sensors, guidewire, optical fiber camera) described herein and/or may beused for any of the functions described herein (e.g., fluid delivery,blood sample extraction).

The system may include a controller, which may be part of any of thecontrol units described herein. Each of the components of the system maybe operably coupled to the controller, and the controller may manageoperation of electrodes during nerve stimulation, control the gatheringof information by various sensors and electrodes, and control fluiddelivery or extraction. It should be understood that the various modulesdescribed herein may be part of a computing system and are separated inFIG. 9 for explanatory purposes only; it is not necessary for themodules to be physically separate.

The electrodes may be electronically coupled to switching electronics,which may be communicably coupled to the controller. As shown in FIG. 9,a portion of the electrodes may be distal electrodes, and a portion ofthe electrodes may be proximal electrodes. Some electrodes may bepositioned on separate catheters. The hub also may be connected toswitching electronics and may be used as an electrode.

The electrodes may be used for both electrically stimulating nerves andfor gathering physiological information. When being used for nervestimulation, a first combination of electrodes (e.g., one, two, three,or more electrodes) may be electrically coupled to a first stimulationmodule channel for stimulation of a first nerve (e.g., the right phrenicnerve) and a second combination of electrodes (e.g., one, two, three, ormore electrodes) may be electrically coupled to a second stimulationmodule channel for stimulation of a second nerve (e.g., the vagusnerve). There may also be a third or fourth channel to stimulate morenerves or muscles. Electrical signals may be sent from the first andsecond stimulation module channels to the electrode combinations tocause the electrodes to stimulate the nerves. In other examples, morethan two electrode combinations (e.g., 3, 4, or more) may be used tostimulate one or more target nerves, and the system may include morethan two stimulation module channels.

The electrodes may be further configured to sense physiologicalinformation from a patient, such as nerve activity, ECG, or electricalimpedance, as will be described further below. When being used forsensing, one or more of electrodes may be electronically coupled to asignal acquisition module. The signal acquisition module may receivesignals from electrodes.

The switching electronics may selectively couple electrodes to firststimulation module channel, the second stimulation module channel, orthe signal acquisition module. Switching electronics may change whichelectrodes are used for stimulation and which are used for sensing atany given time. In one example, any electrode can be used for nervestimulation and any electrode can be used for sensing functionsdescribed herein. In other words, each electrode may be configured tostimulate nerves, and each electrode may be configured to sensephysiological information.

The signal acquisition module may further be coupled to one or moresensors configured to gather physiological information from a patient.For example, the system may include one or more of a blood gas sensor ora pressure sensor. These sensors may be located in lumens of thecatheter, outside of the patient in fluid communication with a lumen, onan outer surface of the catheter, or in any other suitable location. Inone example, the blood gas sensor may be housed in or fluidly connectedto a lumen, while the pressure sensor may be housed in or fluidlyconnected to another lumen. The blood gas sensor may measure the amountof O₂ or CO₂ in the patient's blood. The pressure sensor may measure thecentral venous pressure (CVP) of the patient.

The signal acquisition module may transmit the signals received from oneor more of electrodes, the blood gas sensor, and/or the pressure sensorto the appropriate processing/filtering module of the system. Forexample, signals from the pressure sensor may be transmitted to acentral venous pressure signal processing/filtering module, where thesignals are processed and filtered to aid in interpretation of CVPinformation. Similarly, signals from the blood gas sensor may betransmitted to a blood gas signal processing/filtering module forprocessing and filtering to determine blood gas levels. Signals fromelectrodes, when they are used for sensing, may be sent to a nervesignal processing/filtering module, an ECG signal processing/filteringmodule, or an impedance signal processing/filtering module, asappropriate. Signals from electrodes or other sensors may be sent to anamplification module, if necessary, to amplify the signals prior tobeing sent to the appropriate processing/filtering module.

Exemplary Methods for Preventing or Treating Brain Injury

The systems and methods described herein may prevent, modulate, control,or treat brain injury while pacing the diaphragm. The brain injury maybe caused by mechanical ventilation. The systems and methods may performtests on a brain function and/or a status of vagus nerve stimulation.Based on the results of the tests, one or more phrenic nerves and/orvagus nerves may be stimulated. Stimulation of the nerves may reduceinflammation in the brain. Alternatively or additionally, one or morenerves (e.g., vagus) may be blocked using signals from electrodes toblock aberrant signaling from the brain.

In one exemplary therapy session, catheter 12 may be positioned in thevasculature to extend adjacent or across the left and right phrenicnerves 26, 28. Appropriate distal and proximal electrode pairs may beselected to cause a contraction of the respiratory muscle, e.g., boththe left and right hem i-diaphragm muscles. The operator (e.g.,physician or patient) may set the stimulation pulse train length atabout 1.2 seconds, a pulse amplitude to about 100% of a threshold value,and an initial pulse width to about 100% of a threshold value. Pulseparameters can be adjusted to achieve the desired level of musclecontraction and reduction in positive lung pressure from an externalrespiratory support device 88. The pulse width can be modulated betweenstimulation pulses in the stimulation pulse train. In some cases, thepulse amplitude can be modulated between stimulation pulses in thestimulation pulse train. Using the remote hand held controller 20, theoperator may provide a therapy set of 10 stimulation pulse trains. Insome examples, each of the stimulation pulse trains may be timed tocoincide with a breath delivered by a mechanical ventilator or thepatient's spontaneous breath.

In some embodiments, the system can communicate directly with amechanical ventilator, or other external respiratory support system(e.g., external respiratory support 88), to coordinate the therapydelivery with the support provided by the external device. As previouslydescribed, sensors detecting activity from diaphragm muscles, nerves(e.g. phrenic nerves, vagus nerves, etc.) or other patient monitors orrespiratory support devices can be used to trigger stimulation and/orbreath delivery from a mechanical ventilator. Also, as a non-limitingexample, the systems described herein may be operably connected (e.g.,hardwired, wireless, etc.) to receive a signal from the mechanicalventilator indicating the initiation of a breath to the patient, and thesystems can synchronize the delivery of the stimulation pulse train tocoordinate with a desired phase of the breath. In another example, anoperator may set the stimulation parameters and ask the patient toactivate their breathing muscles. The operator may then coordinate thetrigger of electrical stimulation with the patient efforts to providemaximum exercise of the muscles. In another example, externalrespiratory support 88 can be reduced or even eliminated during aportion of or all of the delivery of a stimulation set or stimulationsession.

In some examples, 10 stimulations pulse trains are provided. The pulsetrains can be timed to 10 sequential breaths, or the operator may skipone or more breaths to allow the patient to rest periodically betweenstimulations. After the 10 stimulation pulse trains are delivered, thepatient may be allowed to rest for a period of time, for example 30seconds to 5 minutes. After a suitable rest, the operator can initiate asecond set, for example 10 breaths, again followed by a resting period.The operator can deliver several sets, e.g., 4 sets, that each includes10 stimulations. Each stimulation may cause a muscle contraction, for atotal of 40 muscle contractions over a 1- to 15-minute period. Thedesired number of stimulations for a session may be delivered in asingle set, if needed. The patient may then be permitted to rest (e.g.,for one or more hours), and in some cases at least 3 hours, andpotentially as long as 24 or 48 hours before beginning another therapysession. In some instances, two to three, or more, therapy sessions aredelivered each day. Regardless, the number of stimulations provided tothe respiratory muscles may be a small fraction of the breaths requiredby the patient each day. In the previously-described example of 40stimulations/day, the number of stimulations delivered is approximatelyless than 0.2% or about 0.2% of the breaths taken by or delivered to thepatient per day.

In one example, the stimulation parameters may be kept the same from onestimulation that causes muscle contraction to the next stimulation, fromone therapy set to the next therapy set, from one session to the nextsession, or from one day to the next day. In other examples, one of theparameters, such as the stimulation amplitude, the stimulationfrequency, the stimulation hold time, or the resistance of the breathingcircuit, may be increased or decreased between two stimulations thatcause muscle contractions, between two sets, between two sessions, orbetween two days. The factors to consider while changing parameters maybe patient tolerance, unintended stimulation of other structures,fatigue, or a desire for increased strength.

In another example of a therapy session, stimulation signals may bedelivered over a total period of time of approximately 2 hours or less,during one or more therapy sessions during that total of 2 hours orless, during a 24-hour period. In another example, stimulation signalsmay be delivered over a total period of time of 5 hours or less during a24-hour period.

In other examples of therapy sessions, stimulation signals may bedelivered to contract one or more respiratory muscles for no more than:20% of the breaths taken by or delivered to the patient in a 24-hourperiod; 10% of the breaths taken by or delivered to the patient in a24-hour period; 2% of the breaths taken by or delivered to the patientin a 24-hour period; or 0.2% of the breaths taken by or delivered to thepatient in a 24-hour period.

In another example, a brief stimulation therapy session lastingapproximately 3 to 10 minutes may be delivered 12 to 24 times over a24-hour period; 6 to 12 times over a 24-hour period; or once in a24-hour period.

In another example, therapy sessions may be administered until thepatient no longer requires external respiratory support; or up to 48hours after the time at which the patient no longer requires, or is nolonger receiving, external respiratory support.

Various examples of the subject disclosure may be implemented soon afterthe patient begins using external respiratory support (e.g., mechanicalventilation) to help reduce the loss of strength and or endurance of arespiratory muscle. Various examples of this disclosure can be used tohelp reduce the level of injury to a patient's lungs, heart, brainand/or other organs of the body. It is contemplated that a stimulationwith every breath, or alternatively a majority of breaths, may provide adesired level of protection.

The systems described herein can be programmed to vary the profile ofthe stimulation pulse trains from time to time. For example, every tenthstimulation pulse train can be programmed to be longer than the othersto produce a deeper or longer breath (e.g., sigh breath). In this case,the duration of the stimulation pulse train between two adjacent pulsetrains will vary.

In some examples, therapy may be continued and steps related toactivating the stimulator and ceasing activation of the stimulator maybe repeated until MIP reaches a pre-determined value.

Furthermore, steps of any therapy treatment described herein may becarried out with respect to more than one nerve and more than onerespiratory muscle. Stimulations of multiple nerves (and one or morerespiratory muscles) may be synchronized so that the patient's muscle ormuscles are stimulated at the same time. To achieve thissynchronization, two or more combinations of selected electrodes may beactivated at the same time during a therapy session. For example, if thefirst set of electrodes emits electrical signals up to 100 times, thesecond set of electrodes may emit electrical signals up to 100 times,with each emission of the second set corresponding to an emission of thefirst set of electrodes. In one example, the first and second sets ofelectrodes may be used to stimulate the left and right phrenic nerves tocause synchronized contractions of the left and right hemi-diaphragms.In another example, the first set may be used to stimulate thediaphragm, and the second set may be used to stimulate the intercostalmuscles. The diaphragm and the intercostal muscles may be stimulatedsimultaneously. Alternatively, the diaphragm and the intercostal musclesmay be stimulated out of phase. For example, when the externalintercostal muscles are stimulated, the diaphragm may be stimulatedsimultaneously with the external intercostal muscles. When the internalintercostal muscles are stimulated, the diaphragm and the internalintercostal muscles may be stimulated out of phase. Both stimulationsmay occur at the same time in the patient breath cycle. In yet anotherexample, the patient's nerves/muscles may be stimulated during aninspiratory period of the patient's ventilator or other externalrespiratory support.

While most examples described herein consider that a therapy sessionwill be delivered by a health care professional, other approaches oftherapy delivery may be utilized that also deliver infrequentrespiratory muscle stimulation to build strength. As a non-limitingexample, a closed-loop automated example of the system of thisdisclosure can be designed to deliver a stimulation to a respiratorymuscle at a specific duty cycle such as 1 stimulation for every Xbreaths, where X could range from 10 to 1000. This approach may providefor periodic muscle stimulation with a predetermined number of restingbreaths in between. X may be as small as 1 and as large as 10,000 invarious examples. When using the systems and methods described herein toprevent respiratory muscle atrophy as well as lung and brain injury, thestimulations can be provided more frequently, potentially as often asevery breath.

Various electrodes may be used to stimulate nerves and/or muscles asdescribed in this disclosure. As examples, the stimulators describedherein may include one or more of: nerve stimulation electrodes,endotracheal electrodes, endoesophageal electrodes, intravascularelectrodes, transcutaneous electrodes, intracutaneous electrodes,electromagnetic beam electrodes, balloon-type electrodes, basket-typeelectrodes, umbrella-type electrodes, tape-type electrodes, suction-typeelectrodes, screw-type electrodes, barb-type electrodes, bipolarelectrodes, monopolar electrodes, metal electrodes, wire electrodes,patch electrodes, cuff electrodes, clip electrodes, needle electrodes,or probe electrodes. Furthermore, the stimulation energy may bedelivered by an energy form that includes at least one of mechanical,electrical, ultrasonic, photonic, or electromagnetic energy.

While principles of the present disclosure are described herein withreference to illustrative embodiments for particular applications, itshould be understood that the disclosure is not limited thereto. Thosehaving ordinary skill in the art and access to the teachings providedherein will recognize additional modifications, applications,embodiments, and substitution of equivalents all fall within the scopeof the embodiments described herein. Accordingly, the invention is notto be considered as limited by the foregoing description.

We claim:
 1. A method for treating a subject, comprising: obtaining a test result reflecting a condition of a brain in the subject; determining a stimulation parameter based on the test result; and stimulating a nerve based on the stimulation parameter, wherein stimulation of the nerve assists or causes contraction of a respiratory muscle in the subject.
 2. The method of claim 1, wherein the nerve is a first nerve, and the method further comprises stimulating a second nerve, wherein stimulation of the second nerve initiates a biological response in the brain that reduces a level of a causing factor of a brain injury.
 3. The method of claim 2, wherein the second nerve is a vagus nerve.
 4. The method of claim 2, wherein stimulation of the second nerve affects signaling from the second nerve to the brain or a lung in the subject.
 5. The method of claim 2, wherein the second nerve is stimulated by an external nerve stimulator.
 6. The method of claim 5, wherein the external nerve stimulator is positioned on a skin area adjacent to a vagus nerve in the subject.
 7. The method of claim 2, wherein the second nerve is stimulated by an implantable nerve stimulator.
 8. The method of claim 2, further comprising stimulating a third nerve.
 9. The method of claim 8, wherein the second nerve is a left vagus nerve, and the third nerve is a right vagus nerve.
 10. The method of claim 2, wherein the second nerve is stimulated by manual, mechanical, electrical, ultrasonic, or electromagnetic energy.
 11. The method of claim 1, wherein the test result is from imaging the brain.
 12. The method of claim 1, wherein the test result comprises a level of an inflammation- or pain-related protein in blood of the subject.
 13. The method of claim 1, wherein the nerve is a phrenic nerve, and the respiratory muscle is a diaphragm muscle.
 14. The method of claim 1, further comprising performing a test that provides the test result.
 15. The method of claim 1, stimulating the nerve comprises inserting a catheter with one or more electrodes in a blood vessel of the subject, and positioning the one or more electrodes proximate the nerve.
 16. The method of claim 1, further comprising ventilating the subject with a mechanical ventilator, wherein the test result comprises an effect of ventilation on the brain.
 17. The method of claim 16, further comprising stimulating a second nerve during at least a portion of a ventilation inspiration period.
 18. The method of claim 1, wherein the nerve is a first nerve, and the method further comprises inhibiting transmission of an aberrant signal by a second nerve.
 19. A system, comprising: a processor configured to: receive a test result reflecting a condition of a brain in a subject; and determine a stimulation parameter based on the test result; and a stimulator configured to stimulate a nerve based on the stimulation parameter, wherein stimulation of the nerve assists or causes contraction of a respiratory muscle in the subject.
 20. The system of claim 19, further comprising a mechanical ventilator.
 21. The system of claim 19, further comprising one or more switches operatively connected to the processor, the one or more switches being configured to regulate stimulation output to the stimulator.
 22. The system of claim 19, further comprising a sensor configured to detect a cardiac event, a respiratory event, a catheter location, a blood pressure, or a level of an inflammatory agent.
 23. The system of claim 22, wherein the stimulator is in communication with the sensor.
 24. The system of claim 19, wherein the stimulator comprises an intravascular catheter having a first set of electrodes configured to stimulate a right phrenic nerve and a second set of electrodes configured to stimulate a left phrenic nerve.
 25. The system of claim 19, wherein the stimulator is configured to affect signaling of a phrenic nerve, signaling of a vagus nerve, or a combination thereof.
 26. A method for treating a subject, comprising: stimulating a first nerve with a first stimulator to assist or cause contraction of a respiratory muscle in the subject; and stimulating a second nerve with the first stimulator or a second stimulator to reduce a level of a causing factor of a brain injury.
 27. The method of claim 26, further comprising stimulating a third nerve with the first stimulator, the second stimulator, or a third stimulator to assist or cause contraction of the respiratory muscle in the subject.
 28. The method of claim 27, wherein stimulation of the first nerve is in synchrony with stimulation of the third nerve.
 29. The method of claim 26, wherein stimulation of the first nerve is coordinated with stimulation of the second nerve.
 30. The method of claim 26, wherein stimulation the first nerve is in synchrony with stimulation of the second nerve.
 31. The method of claim 26, wherein the causing factor of the brain injury is inflammation in the brain.
 32. The method of claim 26, further comprising ventilating the subject with a mechanical ventilator.
 33. The method of claim 32, wherein the second nerve is stimulated during at least a portion of a ventilation inspiration period.
 34. The method of claim 26, wherein the first nerve is a phrenic nerve, and the second nerve is a vagus nerve.
 35. The method of claim 26, wherein the respiratory muscle is a diaphragm muscle.
 36. The method of claim 26, wherein stimulation of the second nerve is performed while the first nerve is not stimulated by the first stimulator.
 37. The method of claim 26, wherein the first stimulator comprises an intravascular catheter having a set of electrodes configured to stimulate a phrenic nerve.
 38. The method of claim 26, wherein the second stimulator comprises an intravascular catheter having a set of electrodes configured to stimulate a vagus nerve.
 39. A system comprising: an electrode configured to stimulate a first nerve to assist or cause contraction of a respiratory muscle in the subject; and a stimulator configured to stimulate a second nerve to reduce a level of a causing factor of a brain injury.
 40. The system of claim 39, wherein the stimulator comprises an intravascular catheter having one or ore electrodes configured to stimulate a vagus nerve.
 41. The system of claim 39, further comprising a catheter configured for intravascular insertion, wherein the catheter comprises a first plurality of electrodes and a second plurality of electrodes.
 42. A method for treating a subject, comprising: stimulating a first nerve with a stimulator to assist or cause contraction of a respiratory muscle in the subject; obtaining a test result of a vagus nerve activity in the subject; generating a stimulation parameter based on test result; and stimulating at least one of the first nerve and a second nerve based on the stimulation parameter.
 43. The method of claim 42, wherein the second nerve is a vagus nerve, and stimulating at least one of the first nerve and the second nerve based on the stimulation parameter includes stimulating the second nerve based on the stimulation parameter.
 44. The method of claim 42, wherein the first nerve is a first phrenic nerve, and the second nerve is a second phrenic nerve.
 45. The method of claim 42, wherein the test result is obtained by testing heart blood flow, testing peripheral blood flow, testing blood pressure, imaging, or assessing inflammation- or pain-related molecules in blood of the subject.
 46. A system comprising: a first nerve stimulator configured to stimulate a first nerve, wherein stimulation of the first nerve assists or causes contraction of a respiratory muscle in the subject; and a processor configured to: receive a test result of a vagus nerve activity in the subject, and generate a stimulation parameter based on the test result; and a second nerve stimulator configured to stimulate a second nerve based on the stimulation parameter. 